Anaplastic Lymphoma Kinase (ALK) is one of the receptor tyrosine kinases belonging to insulin receptor family (Non-Patent Document Nos. 1 and 2).
It was reported that, due to gene alteration of ALK (translocation, point mutation and gene amplification), an abnormal activation of ALK is eventually involved in oncogenesis.
For example, in lung cancer, ALK forms EML4-ALK due to chromosomal translocation, leading to constitutive activation of tyrosine kinase, and it acquires a tumorigenic activity (Non-Patent Document 1). In addition, the ALK translocation were reported in systemic anaplastic large cell lymphoma (ALCL) and inflammatory myofibroblastic tumors (IMTs) (Non-Patent Document Nos. 3 and 4), and esophageal cancer (Non-Patent Document 5). It was also found that active point mutation (approximately 10%) or gene amplification of ALK is involved in oncogenesis of neuroblastoma (Non-Patent Document Nos. 6 and 7).
On the other hand, it was also reported in tumors activated by pleiotrophin (PTN) or midkine (MK) (Non-Patent Document Nos. 8 and 9), both a ligand for ALK.
Further, from the study using ALK knock-out mouse, it was suggested that an inhibitor for ALK is useful as an anti-depression agent or as a preventive or therapeutic agent for cognitive function disorders (Non-Patent Document 10 and Patent Document 1).
Therefore, a compound having an inhibitory activity on ALK will be very useful for the prevention and treatment of cancer, depression and cognitive function disorders, etc.
Meanwhile, as an ALK inhibiting material, there are some compounds among multi-kinase inhibitors which have an inhibitory activity on ALK as one of their activities. For example, as an inhibitor for c-MET (mesenchymal-epithelial transition factor) and ALK, PF02341066 having a 2-aminopyridine structure was reported (Patent Document 2, Non-Patent Document Nos. 11 and 12). As an inhibitor for FAK, ZAP70, IGF-1R and ALK, etc., NVP-TAE684 having a 2,4-diaminopyrimidine structure was reported (Patent Document 3 and Non-Patent Document 13). In addition, 2,4-diaminopyrimidines and 2,4-diaminoquinazolines (Patent Document 4), pyridopyrazines (Patent Document 5), pyrazolo[3,4-C]isoquinolines (Patent Document 6), thiazoles (Patent Document 7), tricyclic compounds (Patent Document 8), and indazoles (Patent Document 9) and the like have been reported.
However, the tetracyclic compounds of the present invention are not disclosed in any of the documents described above.
As a tetracyclic compound exhibiting an anti-tumor activity, tetracyclic compounds comprising carbazole structure like ellipticine are known.
However, their action mechanism is based on interaction with DNA to exhibit cell toxicity (Non-Patent Document 15), and there is no description at all regarding the activity of inhibiting ALK by the tetracyclic compounds.